Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
44 巻 , 12 号
選択された号の論文の17件中1~17を表示しています
Reviews
  • Yuru Wang, Minyue Bao, Chuping Hou, Yue Wang, Liwei Zheng, Yiran Peng
    2021 年 44 巻 12 号 p. 1801-1809
    発行日: 2021/12/01
    公開日: 2021/12/01
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    Temporomandibular disorder (TMD) is an oral dentofacial disease that is related to multiple factors such as disordered dental occlusion, emotional stress, and immune responses. In the past decades, tumor necrosis factor-alpha (TNF-α), a pleiotropic cytokine, has provided valuable insight into the pathogenesis of TMD, particularly in settings associated with inflammation. It is thought that TNF-α participates in the pathogenesis of TMD by triggering immune responses, deteriorating bone and cartilage, and mediating pain in the temporomandibular joint (TMJ). Initially, TNF-α plays the role of “master regulator” in the complex immune network by increasing or decreasing the production of other inflammatory cytokines. Then, the effects of TNF-α on cells, particularly on chondrocytes and synovial fibroblasts, result in pathologic cartilage degradation in TMD. Additionally, multiple downstream cytokines induced by TNF-α and neuropeptides can regulate central sensitization and inflammatory pain in TMD. Previous studies have also found some therapies target TMD by reducing the production of TNF-α or blocking TNF-α-induced pathways. All this evidence highlights the numerous associations between TNF-α and TMD; however, they are currently not fully understood and further investigations are still required for specific mechanisms and treatments targeting specific pathways. Therefore, in this review, we explored general mechanisms of TNF-α, with a focus on molecules in TNF-α-mediated pathways and their potential roles in TMD treatment. In view of the high clinical prevalence rate of TMD and damage to patients’ QOL, this review provides adequate evidence for studying links between inflammation and TMD in further research and investigation.

    Editor’s picks

    This article concludes the underlying responses of inflammation in temporomandibular disorder(TMD), a complex and common oral dentofacial disease. One of the most involved inflammatory cytokines--TNF-α, has effects on TMD and its inflammation. These effects are summarized comprehensively and explicitly as triggering immune responses, degenerating bone and cartilage and mediating pain of temporomandibular joint. This review gives an insight into this connection between TNF-α and TMD, which may highlight TNF-α as a new therapeutic target for TMD treatment and therefore provide new insight for therapeutic intervention for TMD.

  • Tadashi Matsuda, Kenji Oritani
    2021 年 44 巻 12 号 p. 1810-1818
    発行日: 2021/12/01
    公開日: 2021/12/01
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    The signal-transducing adaptor protein (STAP) family, including STAP-1 and STAP-2, contributes to a variety of intracellular signaling pathways. The proteins in this family contain typical structures for adaptor proteins, such as Pleckstrin homology in the N-terminal regions and SRC homology 2 domains in the central regions. STAP proteins bind to inhibitor of kappaB kinase complex, breast tumor kinase, signal transducer and activator of transcription 3 (STAT3), and STAT5, during tumorigenesis and inflammatory/immune responses. STAP proteins positively or negatively regulate critical steps in intracellular signaling pathways through individually unique mechanisms. This article reviews the roles of the novel STAP family and the possible therapeutic applications of targeting STAP proteins in cancer.

    Editor’s picks

    The signal-transducing adaptor protein (STAP) family, including STAP-1 and STAP-2, contributes to a variety of intracellular signaling pathways. STAP proteins bind to IκB kinase complex, BRK, STAT3, and STAT5, during tumorigenesis and inflammatory/immune responses. STAP proteins positively or negatively regulate critical steps in intracellular signaling pathways through individually unique mechanisms. In this review, the authors describe that STAP proteins are involved in the development and/or progression of some types of malignancies. The authors further describe the possible therapeutic applications of targeting STAP proteins in cancer.

Communication to the Editor
  • Yoshitaka Saito, Yoh Takekuma, Yoshito Komatsu, Mitsuru Sugawara
    2021 年 44 巻 12 号 p. 1819-1823
    発行日: 2021/12/01
    公開日: 2021/12/01
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    We have reported that a strict denosumab administration management system with oral calcium/vitamin D supplementation attenuates denosumab-induced hypocalcemia in 158 cancer patients with bone metastasis. In this report, 27.8% of the patients experienced hypocalcemia, including 0.6% with grade 2. So far, the risk factors for ≥grade 2 hypocalcemia incidence have been identified in denosumab-treated cancer patients, including patients without calcium/vitamin D supplementation. Therefore, the present study aimed to reveal the factors that affect all-grade hypocalcemia incidence with calcium/vitamin D supplementation and team medical care according to the management system. A receiver operating characteristic curve analysis suggested that the cutoff of baseline serum calcium level for all-grade hypocalcemia incidence was 9.3 mg/dL. Multivariate analysis revealed that age ≥65 years (odds ratio, 95% confidence interval: 2.57, 1.11–5.95, p = 0.03), grade 1 or higher serum alkaline phosphatase elevation (3.70, 1.71–8.00, p < 0.01), an adjusted serum calcium level of less than 9.3 mg/dL (3.21. 1.25–8.24, p = 0.02) at baseline, and co-administration of cytotoxic agents (2.33, 1.06–7.11, p = 0.03) are risk factors for the incidence of all-grade hypocalcemia. However, renal dysfunction, which has been suggested to be a risk factor in previous reports, was not a factor. In conclusion, we revealed the risk factors for all-grade hypocalcemia in calcium/vitamin D supplementation and awareness, as demonstrated by the management system. Moreover, renal dysfunction was not a risk factor in our strict denosumab administration management system. Our results support the value of early detection of hypocalcemia incidence to guide the selection of an appropriate management strategy.

Regular Articles
  • Masaru Doshi, Shiro Watanabe, Yujin Natori, Makoto Hosoyamada, Yutaka ...
    2021 年 44 巻 12 号 p. 1824-1831
    発行日: 2021/12/01
    公開日: 2021/12/01
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    Thyroid hormones (THs) have been suggested to play an important role in both physiological and pathological events in the central nervous system. Hypothyroidism, which is characterized by low levels of serum THs, has been associated with aggravation of ischemic neuronal injuries in stroke patients. We hypothesized that administration of T3, the main active form of THs, may attenuate the ischemic neuronal injuries. In mice, global cerebral ischemia (GCI), which is induced by transient occlusion of the bilateral common carotid artery, causes neuronal injuries by inducing neuronal death and activating inflammatory responses after reperfusion in the hippocampus. In this study, we examined the effect of T3 administration on DNA fragmentation induced by neuronal death and the activation of inflammatory cells such as astrocytes and microglia in the hippocampus following GCI. The content of nucleosomes generated by DNA fragmentation in the hippocampus was increased by GCI and further increased by T3 administration. The protein expression levels of glial fibrillary acidic protein (GFAP), an astrocytic marker, and Ionized calcium binding adaptor protein 1 (Iba1), a microglial marker, in the hippocampus were also increased by GCI and further increased by T3 administration. The levels of T3 in both the serum and hippocampus were elevated by T3 administration. Our results indicate that T3 administration aggravates GCI–reperfusion injury in mice. There may be an increased risk of aggravation of ischemic stroke by the excessive elevation of T3 levels during the drug treatment of hypothyroidism.

  • Misa Muraoka, Moeka Ohno, Makoto Tateishi, Hideyuki Matsuura, Kazuya N ...
    2021 年 44 巻 12 号 p. 1832-1836
    発行日: 2021/12/01
    公開日: 2021/12/01
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    γ-Glutamylcysteine (γ-EC) has antioxidant properties similar to those of glutathione (GSH) and acts as its precursor in mammals. There are a few procedures for the production of γ-EC, such as chemical synthesis or enzymatic synthesis from glutamate and cysteine; however, they are very costly and not suitable for industrial production. A phytochelatin synthase-like enzyme derived from Nostoc sp. Pasteur Culture Collection 7120 (NsPCS) catalyzes the hydrolysis of GSH to γ-EC and glycine in the absence of ATP or other additives. Our research aims to establish an alternative γ-EC production procedure with low cost and high productivity. To this end, we optimized the reaction conditions of NsPCS and characterized its properties in this study. We found that 200 mM potassium phosphate buffer, pH 8.0, at 37 °C, had the highest NsPCS activity among the conditions we tested. Under these conditions, NsPCS had a Km of 385 µM and a Vmax of 26 mol/min/mg-protein. In addition, NsPCS converted 100 mM GSH into γ-EC with high yields. These results suggest that the NsPCS reaction has great potential for the low-cost, industrial-scale production of γ-EC.

    Editor’s picks

    Gamma-glutamylcysteine (g-EC) has antioxidant properties similar to those of glutathione (GSH) and acts as its precursor in mammals. In this paper, the reaction conditions of the phytochelatin synthase-like enzyme derived from Nostoc sp. (NsPCS) which hydrolyzes GSH to g-EC was optimized, resulting that high yield conversion from 100 mM GSH to g -EC was achieved in the absence of ATP and other additives. These results suggest that the NsPCS reaction has great potential for the low-cost industrial-scale production of g-EC from GSH.

  • Ching-Yi Yiu, Yu-Jhe Chiu, Tsuey-Pin Lin
    2021 年 44 巻 12 号 p. 1837-1842
    発行日: 2021/12/01
    公開日: 2021/12/01
    [早期公開] 公開日: 2021/10/06
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    Epstein-Barr virus (EBV), a human herpesvirus, is several human lymphoid malignancies-associated. Our earlier study found the effect of Polygonum cuspidatum root on promoting EBV-positive apoptosis. Therefore, this study investigated the effects of the Polygonum cuspidatum ethyl acetate subfraction containing emodin on EBV gene expression and anti-EBV tumor cells. Resultantly, the the Polygonum cuspidatum ethyl acetate subfraction containing emodin (F3a) promoted Raji cell death (50% cytotoxic concentration, CC50: 12.08 µg/mL); the 12.5 µg/mL F3a effect transcribed BRLF1 and BNLF1 and increased latent membrane protein 1 (LMP1), which may reduce the intracellular phospho-extracellular signal-regulated kinase (ERK) and phospho-inhibitor of Nuclear factor kappa B α (IκBα). Meanwhile, the Raji cells increased the intracellular reactive-oxygen species (ROS), activated the apoptosis-related proteins, cleaved caspase 3 and poly(ADP-ribose)polymerase (PARP), and increased the apoptosis percentage. Therefore, the Polygonum cuspidatum ethyl acetate subfraction containing emodin could be a therapeutic drug for EBV-related tumors.

  • Kazuhiro Katayama, Ayane Nishihata
    2021 年 44 巻 12 号 p. 1843-1850
    発行日: 2021/12/01
    公開日: 2021/12/01
    [早期公開] 公開日: 2021/10/01
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    Fms-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase 1/2 (IDH1/2) mutations drive malignancy in acute myeloid leukemia (AML), which accounts for approximately 40% of AML cases. Treatment with FLT3 or IDH1/2 inhibitors is used for such patients; however, it is not considered for most patients with AML who lack mutations on the respective genes. In this study, p90 ribosomal S6 kinase (RSK) was found to serve as a new therapeutic target in various AMLs with or without FLT3 mutations. BI-D1870, a potent inhibitor of RSK, significantly suppressed the proliferation of AML cell lines, among which three encoded wild-type FLT3 and three contained FLT3 driver mutations, compared with chronic myeloid leukemia K562 cells or other adherent cancer cells. BI-D1870 inhibited protein synthesis by dephosphorylating the p70 S6 kinase and eukaryotic initiation factor 4E-binding protein 1 in all AML cells except KG-1a cells. Meanwhile, the expression of microtubule-associated protein light chain 3B-I and -II increased in KG-1a cells treated with BI-D1870. BI-D1870 induced caspase-dependent apoptosis in all AML cells, including KG-1a cells. We next investigated the synergistic effect of BI-D1870 with cytarabine, a traditional anticancer drug used in AML. Synergistic effects of BI-D1870 and cytarabine were not observed in any of the cell lines. The findings suggested that BI-D1870 alone exerts an adequate antiproliferative effect on AML with or without FLT3 mutations and serves as a novel AML therapeutic agent.

  • Hiromi Tsushima, Kazuyo Yamada, Daisuke Miyazawa, Takeshi Ohkubo, Mako ...
    2021 年 44 巻 12 号 p. 1851-1859
    発行日: 2021/12/01
    公開日: 2021/12/01
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    The physical characteristics and behavior of the ATP-binding cassette (ABC) A1, A7, and apolipoprotein (apo) E knockout (KO) mice with lipid transport dysfunction were investigated. These KO mice exhibited adequate growth, and their body masses increased steadily. No remarkable changes were observed in their blood pressure and heart rate. However, there was a slight increase in the heart rate of the ABCA7 KO mice compared with that of the wild-type (WT) mice. ABCA1 and apoE KO mice showed hypo- and hyper-cholesterol concentrations in the plasma, respectively. With regard to the cerebrum, however, the weight of the ABCA1 KO mice was lighter than those of the other genotypes. Furthermore, the cholesterol, triglyceride and phospholipid concentrations, and fatty acid composition were generally similar. Compared with the WT mice, ABCA1 KO mice stayed for a shorter time in the closed arm of the elevated plus maze, and performed worse in the initial stage of the Morris water maze. To thermal stimuli, the ABCA1 and apoE KO mice showed hyper- and hypo-sensitivities, respectively. Only the response of the ABCA1 KO mice was significantly inhibited by pretreatment with indomethacin. A low concentration of the prostaglandin E metabolites was detected in the plasma of the ABCA1 KO mice. Thus, ABCA1 is thought to play a specific role in the neural function.

  • Asami Mori, Ryo Namekawa, Kenji Sakamoto, Kunio Ishii, Tsutomu Nakahar ...
    2021 年 44 巻 12 号 p. 1860-1865
    発行日: 2021/12/01
    公開日: 2021/12/01
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    An electrical communication between the endothelial and smooth muscle cells via gap junctions, which provides the signaling pathway known as endothelium-dependent hyperpolarization (EDH), plays a crucial role in controlling the vascular tone. In this study, we investigated the role of gap junctions in the acetylcholine (ACh)-induced EDH-type dilation of rat retinal arterioles in vivo. The dilator response was evaluated by measuring the diameter of retinal arterioles. Intravitreal injection of gap junction blockers (18β-glycyrrhetinic acid and carbenoxolone) reduced the ACh-induced dilation of retinal arterioles. Moreover, the retinal arteriolar response to ACh was attenuated by 18β-glycyrrhetinic acid under treatment with a combination of NG-nitro-L-arginine methyl ester (a nitric oxide (NO) synthase inhibitor; 30 mg/kg) and indomethacin (a cyclooxygenase inhibitor; 5 mg/kg). The NO- and prostaglandin-independent, EDH-related component of ACh-induced dilation of retinal arterioles was prevented by intravitreal injection of iberiotoxin, which inhibits large-conductance Ca2+-activated K+ channels. Furthermore, the combination of 18β-glycyrrhetinic acid and iberiotoxin produced greater attenuation in the EDH-related response than that by the individual agent. Treatment with 18β-glycyrrhetinic acid revealed no significant effect on NOR3 (an NO donor)-induced retinal vasodilator response. These results suggest that gap junctions contribute to the ACh-induced, EDH-type dilation of rat retinal arterioles in vivo.

    Editor’s picks

      Acetylcholine (ACh) stimulates the production of cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs), which activate large-conductance Ca2+-activated K+ (BKCa) channels. The article by Mori et al. provides evidence suggesting that ACh-induced hyperpolarization of endothelial cells transmits to adjacent smooth muscle cells via myoendothelial gap junctions. ACh can also facilitate gap junctional communication between endothelial cells and/or between smooth muscle cells. These pathways contribute to the hyperpolarization and relaxation of vascular smooth muscle cells in rat retinal arterioles.

  • Takanori Kanazawa, Yuki Hoashi, Hisako Ibaraki, Yuuki Takashima, Hiroa ...
    2021 年 44 巻 12 号 p. 1866-1871
    発行日: 2021/12/01
    公開日: 2021/12/01
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    In this study, we focused on a nuclear localization signal (NLS)-based versatile peptide vector, designed by us, combined with electroporation (EP) to establish an efficient gene delivery system to non-dividing or slow growing dendritic cells. We determined the intranuclear transport, gene expression, and cell viability in JAWS II mouse dendritic cells transfected with the green fluorescent protein (GFP) expression plasmid DNA alone (naked pEGFP); positive charged complex of NLS derivative STR-CH2SV40H2C, and pEGFP (binary complex); or negative charged complex of the binary complex with a biocompatible polyanion, γ-polyglutamic acid (ternary complex) combined with or without EP application. Although the binary complex showed higher nuclear transport and GFP expression in the absence of EP than those for naked pEGFP, the combination of EP significantly decreased the cell viability and did not improve the efficiency of compared gene expression. However, in the ternary complex, the intranuclear transport and GFP expression efficiency were significantly higher than those of naked pEGFP and the binary complex when combined with EP, and there was no decrease in cell viability. The results suggest that polyanion-coated ternary complex with EP is useful for non-viral gene delivery system into non-dividing cells for ex vivo gene/cell therapy.

  • Shengquan Hu, Jing Liu, Sikang Chen, Jian Gao, Yubo Zhou, Tao Liu, Xia ...
    2021 年 44 巻 12 号 p. 1872-1877
    発行日: 2021/12/01
    公開日: 2021/12/01
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    FMS-like tyrosine kinase 3 (FLT3) plays a very important role in regulating the proliferation, differentiation and survival of normal hematopoietic stem cells. Internal tandem duplications of the FLT3 gene (FLT3-ITD) mutations are present in 25% of all acute myeloid leukemia (AML) patients and are frequently associated with adverse clinical outcomes. Therefore, FLT3-ITD is a promising target for the treatment of AML. The use of covalent virtual screenings has shown that efficient rational approaches for the rapid discovery of new drugs scaffold. Herein, we report a hybrid virtual screening strategy that led to the discovery of FLT3 inhibitors. Using the combination of non-covalent docking and covalent docking, 8 compounds were found to inhibit FLT3, and G856-8335, S346-0154 are also effective against mutant FLT3. These two compounds also show selectivity to receptor tyrosine kinase (C-KIT), which has the potential for optimization. And this work can be extended to the screening of other covalent inhibitors.

  • Yoshie Tsujiya, Ai Hasegawa, Motohiro Yamamori, Noboru Okamura
    2021 年 44 巻 12 号 p. 1878-1885
    発行日: 2021/12/01
    公開日: 2021/12/01
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    Renal cell carcinoma (RCC) is the most common type of kidney cancer. Given that stage IV RCC is intractable, there is a need for a novel treatment strategy. We investigated the antitumor effects of telmisartan (TEL) and their underlying mechanisms in RCC, including their impact on apoptosis, Akt/mammalian target of rapamycin (mTOR) pathways, and the cell cycle using two human RCC cell lines: 786-O and Caki-2. Cell viability was detected via fluorescence-based assays. Cells were stained with Hoechst 33342 to observe chromatin condensation, and Western blotting was performed to analyze protein expression. The cell cycle was assessed using flow cytometry. Invasion and migration assays were performed using 24-well chambers. TEL induced cell death in a dose-dependent manner and increased the percentage of cells with high chromatin condensation and Bax/Bcl-2 ratio in both cell lines. TEL-induced cell death was attenuated by neither peroxisome proliferator-activated receptor-γ nor -δ inhibitors. Although TEL elevated c-Jun N-terminal kinase levels and p38 phosphorylation rates in Caki-2 cells, as well as extracellular signal-regulated kinase phosphorylation rates in 786-O cells, their inhibitors did not suppress TEL-induced cell death. TEL decreased Akt phosphorylation in 786-O cells and mTOR phosphorylation in both cell lines, increased the population of cells in the G2/M phase, and altered G2/M-related proteins in both cell lines. TEL moderately suppressed cell invasion and migration in 786-O and Caki-2 cells, respectively, and increased cell invasion in Caki-2 cells, suggesting a potential therapeutic role of TEL in RCC.

Notes
  • Masafumi Noda, Narandalai Danshiitsoodol, Takemasa Sakaguchi, Keishi K ...
    2021 年 44 巻 12 号 p. 1886-1890
    発行日: 2021/12/01
    公開日: 2021/12/01
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    A lactic acid bacterial strain, Lactobacillus plantarum SN35N, which has been isolated from the pear, secretes negatively charged acidic exopolysaccharide (EPS) to outside cells. We have previously found that the SN35N-derived acidic EPS inhibits the catalytic activity of hyaluronidase (EC 3.2.1.35) promoting inflammation. The aim of this study is to find other health benefits of EPS. EPS has been found to exhibit an inhibitory effect against the influenza virus (Alphainfluenzavirus Influenza A virus) and feline calicivirus (Vesivirus Feline calicivirus), which is recognized as a model of norovirus. Although more studies on the structure–function relationship of EPSs are needed, SN35N-derived EPS is a promising lead for developing not only anti-inflammatory agents, but also antiviral substances.

  • Masahiro Kaneko, Toru Iizuka, Toshiharu Nakajima
    2021 年 44 巻 12 号 p. 1891-1893
    発行日: 2021/12/01
    公開日: 2021/12/01
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    Asthma is characterized by chronic inflammation of the airway mucosa. As Eucommia ulmoides Oliv. leaf extract (ELE) has been known to have anti-inflammatory properties, herein, we investigated the effect of ELE on interleukin (IL-) 8 production in A549 cells, a human airway epithelial cell line. The addition of ELE 1 h before tumor necrosis factor-alpha (TNFα) stimulation inhibited IL-8 production by A549 cells in a concentration-dependent manner. The addition of geniposidic acid, the main component of ELE, also inhibited IL-8 production. To further investigate the mechanism by which ELE inhibits IL-8 production, the effect of ELE or geniposidic acid on TNFα-stimulated p38 phosphorylation was examined by Western blotting. After 30 min of TNFα stimulation, p38 phosphorylation was inhibited by the addition of ELE or geniposidic acid, suggesting that ELE inhibited IL-8 production in TNFα-stimulated A549 cells by suppressing one of the signal transducers of p38 phosphorylation. These results indicate that ELE can be used as an effective measure against asthma, particularly neutrophilic asthma.

  • Shogo Hamaguchi, Kohei Abe, Momoka Komatsu, Jun Kainuma, Iyuki Namekat ...
    2021 年 44 巻 12 号 p. 1894-1897
    発行日: 2021/12/01
    公開日: 2021/12/01
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    The lusitropic effect of quercetin was examined on isolated ventricular myocardial tissue preparations from normal and streptozotocin-induced diabetic mice. The time required for 90% relaxation of the myocardium, which was prolonged in the diabetic mice, was shortened by quercetin in both normal and diabetic myocardia. This effect of quercetin was completely inhibited by cyclopiazonic acid but not by SEA0400. These results indicated that quercetin accelerates myocardial relaxation through activation of the sarco–endoplasmic reticulum Ca2+-ATPase.

    Editor’s picks

    Diastolic dysfunction is a major cardiac deficit underlying heart failure accompanying hypertension, coronary artery disease, and diabetes mellitus and is partly mediated by impaired myocardial relaxation and Ca2+ handling. Therapeutic agents targeting diastolic dysfunction are not yet clinically available. Quercetin is one of the major flavonoid compounds contained in fruits and vegetables. The authors examined the lusitropic effect of quercetin on isolated ventricular myocardial tissue preparations from normal and streptozotocin-induced diabetic mice and showed that quercetin accelerated myocardial relaxation through activation of the sarco/endoplasmic reticulum Ca2+-ATPase. This finding may lead to the development of novel therapeutic agents of natural origin.

  • Yuto Sasaki, Kodai Saitoh, Kota Kagohashi, Yuichi Kitai, Ryuta Muromot ...
    2021 年 44 巻 12 号 p. 1898-1901
    発行日: 2021/12/01
    公開日: 2021/12/01
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    Signal-transducing adaptor protein-2 (STAP-2) is an adaptor protein involved in inflammatory and immune responses, such as inflammatory bowel disease and allergic responses. In this study, we investigated the role of STAP-2 in the pathogenesis of autoimmune hepatitis. After intravenous injection of concanavalin A (ConA), STAP-2 knock out (KO) mice showed more severe liver necrosis along with substantial lymphocyte infiltration compared to wild type (WT) mice. Serum alanine aminotransferase levels were significantly higher in ConA-injected STAP-2 KO mice than in WT mice. Levels of interferon-γ (IFN-γ), an important factor for liver necrosis, were also significantly increased in sera of STAP-2 KO mice compared to WT mice after ConA injection. Statistically significant upregulation of Fas ligand (FasL) expression was observed in the livers of ConA-injected STAP-2 KO mice compared to WT mice. In accordance with these results, apoptotic signals were facilitated in STAP-2 KO mice compared to WT mice after ConA injection. Correctively, these results suggest that STAP-2 is involved in the pathogenesis of autoimmune hepatitis by regulating the expression of FasL and the production of IFN-γ.

  • Muhammad N. A. Sahid, Shuang Liu, Takeshi Kiyoi, Kazutaka Maeyama, Mas ...
    2021 年 44 巻 12 号 p. 1902-1906
    発行日: 2021/12/01
    公開日: 2021/12/01
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    Mast cell (MC) exocytosis is organized by prenylated protein, including Rab families. Among Rab proteins, Rab3a, Rab27a, and Rab11 are responsible for exocytosis arrangement. Rab3a and Rab27a are contributed to exocytosis by interacting with other exocytosis proteins. Zoledronate administration disrupted the Rab prenylation process that affected its interaction with other proteins, and finally, its function. The present study has investigated the effect of zoledronate on the histamine release (HR) from RBL-2H3 cells. The main focus is to answer the question of whether zoledronate affects Rab27a/Doc2a interaction. Histamine release on RBL-2H3 cells after zoledronate or clodronate administration was measured using HPLC-fluorometry. Dinitrophenylated bovine serum albumin (DNP-BSA) (20 ng/mL) or ionomycin (1 µM) are used as secretagogues. Calcium (Ca2+) influx observation was performed using Fura-2A/M. In situ proximity ligation assay (PLA) is used to investigate Rab27a/Doc2a interaction after bisphosphonates (BPs) treatment. Histamine concentration measurement with HPLC-fluorometry showed that zoledronate (30, 100 µM) inhibited HR from antigen-activated RBL-2H3 cells. Zoledronate showed less inhibition in cells activated with ionomycin. Intracellular Ca2+ concentration and Ca2+ flux rate from the extracellular compartment was not changed by zoledronate administration. No changes in Rab27a/Doc2a interaction after zoledronate treatment. Histamine release inhibition by zoledronate in DNP-BSA-activated RBL-2H3 cells is not related to the disruption of Rab27a/Doc2a interaction and is not involve the change in Ca2+ influx.

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